Obesity is associated with a state of systemic inflammation that underlies the pathogenesis of diabetes and metabolic syndrome and has its genesis in adipose tissue. The cellular and molecular mechanisms underlying adipose tissue inflammation are not well understood. While adipose tissue macrophages (ATM) are central mediators of inflammation and systemic insulin resistance, other leukocytes also play a role. NK cells regulate macrophage function in other disease states, but few prior data study adipose tissue NK cells (ATNK) in the context of obesity and their role in regulating ATM inflammatory responses. ATNK are an understudied cell type and an important putative upstream regulator of ATM- mediated adipose tissue inflammation, and are thus an excellent target for research directed towards manipulating ATM function with the goal of ameliorating obesity-related inflammation and insulin resistance. Our preliminary data demonstrate increased ATNK in obesity and a role for ATNK-derived IFN- in promoting ATM inflammatory responses. Our long-term goal is to develop novel ATNK-based immunotherapy for metabolic disease. The goals of this proposal are: to identify putative pathogenic ATNK subpopulations that are increased in frequency in human obesity, the cytokine stimuli that drive their activation, and their role in regulating inflammation and insulin resistance in human adipose tissue (Aims I, II), and to determine the effect of in vivo ablation of NK cells on systemic inflammation and insulin resistance in obese mice (Aim III). Our central hypotheses are that specific ATNK subpopulations are increased in frequency in human obesity and drive ATM inflammatory responses and insulin resistance, and that in vivo ablation of NK cells will attenuate systemic inflammation and insulin resistance in murine obesity. The rationale for this work is that identification of pathogenic ATNK subpopulations and upstream cytokine stimuli that regulate their function will provide targets for future research directed towards in vivo immunoneutralization of these mediators as a means to attenuate insulin resistance and metabolic disease. PUBLIC HEALTH RELEVANCE: Adipose tissue inflammation underlies numerous obesity-related diseases and elucidation of its mechanisms will guide research directed towards developing therapy for obesity-related metabolic disease. NK cells are understudied cellular mediators of adipose tissue inflammation. This proposal will study the role of NK cells in human adipose tissue inflammation and the efficacy of in vivo systemic NK cell knockdown in murine obesity as first steps towards developing NK cell-based therapy for metabolic disease.